The present invention is related to a method of employing oral TRH (thyrotropin releasing hormone) in order to enhance lactation and to provide for a prolongation of postpartum infertility. More particularly, the present invention is concerned with the specific dosages, the route and timing of administration of oral TRH in order to provide such effects.
Previous methods for the administration of TRH intravenously are described, for example, by J. E. Tyson et al., Science, 177:897 (1972); J. E. Tyson et al., Am. J. Obstet. Gynecol., 116:377 (1973); and J. E. Tyson et al., J. Clin. Endocrinol. Metab., 40:764 (1975), all of which descriptions are incorporated herein by reference. The use of oral TRH is described by A. Zarate et al., J. Clin. Endocrinol. Metab., 43:301 (1976). However, in this latter publication, also incorporated by reference, in which TRH was reported as administered in 20 mg. dosage capsules at intervals of three times a day, the authors concluded that TRH administered orally had no significant effect on the yield or composition of milk.
By the present invention, there is provided an improved method for orally administering TRH in order to enhance lactation and to provide for a prolongation of postpartum infertility. Advantageous results have been obtained in nursing women following full term delivery, as well as in women whose child has been born prematurely. In addition, beneficial results have been obtained in surrogate mothers by a method of treatment in which oral TRH is administered in conjunction with estrogens.
It has been found that women have enjoyed a natural state of infertility for varying periods of time depending upon the duration, frequency and intensity of nipple stimulation. Nipple stimulation has traditionally only occured in women who have wished to breastfeed their infants and indeed, there is evidence in the scientific literature to suggest that women who practice uninterrupted breastfeeding will experience an inability to ovulate for upwards of 24 months following the delivery of their child.
At the same time, however, there is evidence that a 7% incidence of pregnancy can occur in women who "breastfeed". Scientific evidence indicates that the single most important factor in determining the ability of a women to ovulate in the postpartum period is the level of her peripheral prolactin. This level is in turn determined by the frequency, intensity and duration of the nursing stimulus. Since it is impossible to calibrate the nursing interval for all women, it is possible, therefore, to enhance the secretion of prolactin by the use of certain substances. The least noxious of these substances has proven to be thyrotropin releasing hormone (TRH).
The present invention is unique in that it utilizes a well known physiologic fact, namely, that prolactin secretion in women postpartum is significantly elevated and is associated with the enlargement of the prolactin-secreting cells. These cells are at the same time more sensitive to stimulation from very low doses of TRH. Since TRH is also known to release thryotropin, it is of some concern that an additional effect of TRH might be seen on maternal thyroid physiology. This effect, however, has never been seen since the does of TRH necessary to produce a maximum prolactin response is 5 to 10 times lower than that dose required to produce a threshold response from the pituitary gland in terms of thyrotropin secretion. Thus, the use of TRH in postpartum women in low doses is very effective in 95% of instances in elevating the peripheral prolactin concentration.
It has been found that all women who breastfeed effectively must have a basal plasma prolactin concentration in excess of 30 nanograms per milliliter. More than 80% of women who breastfeed have such a level. However, for reasons of decreased frequency of nursing brought about by supplementation of the infants's diet with exogenous food, the prolactin concentration may actually fall below 30 nanograms per milliliter. If this persists for more than 2-3 days, even though a mother may be willing to breastfeed her child, milk production is decreased. At the same time, the decrease in the prolactin level brought about by the decreased frequency of feeding will be associated with a resumption in the secretion of pituitary gonadotropins--those hormones necessary for stimulation of ovarian function.
In accordance with the present invention, it has been found that the administration of 5-10 milligrams of oral TRH, twice a day at intervals of about 12 hours for about 5 days to women whose plasma prolactin falls below 30 ng/ml is associated with an increase secretion of prolactin by the woman and a resumption of milk production with a subsequent increase in milk volume. It has been further shown that suckling-stimulated prolactin release is also enhanced in women taking this dose of TRH twice a day and this in turn increases the production of milk endogenously.
It is thus seen, in accordance with the present invention, that a five day course of oral TRH 5-10 mg twice a day will be associated with an increase in the peripheral plasma prolactin concentration increasing the milk production by the mother and making more milk available to the infant. At the same time, this dose of TRH will provoke an increased prolactin response to the sucking efforts of the child and therefore increse milk production by that woman. The present data suggests that in the dosage levels mentioned, there is little or no effect of TRH on thyroid function in such women, yet the increased secretion of prolactin will further impair fertility by interfering with gonadotropin secretion at the pituitary gland.
Approximately 20% of women, for one reason for another, have difficulty with breastfeeding. Part of this is due to fear of the procedure and part due to an inability of the child to stimulate the nipple adequately due, often, to abnormalities of the lip and the palet of the child. It is to be conceded that breastfeeding in such infants is advantageous and therefore should be supported in any way possible.
A second group of infants that will benefit tremendously from breastfeeding are those born prematurely. Previously, it had not been deemed possible for mothers of premature infants to breastfeed because of a failure of lactation to be initiated. This failure is thought to be due to inadequate preparation of the pituitary gland for the secretion of prolactin. Yet, it has been found in accordance with the present invention that the pituitary prolactin cells can be stimulated to secrete prolactin through the oral administration of TRH. Thus, an additional use of TRH would be in a dose of 10 mg twice a day to mothers who have delivered premature infants. This dosage would elevate the prolactin concentration and would increase the likelihood of the initiation of lactation. It is suggested from present research that such therapy be administered to these women until the maternal mammary milk volume exceeds 300 ml a day. Often, this is easily measurable since the mother is pumping the breast in order to give the milk to the child by some artificial means. The successful use of TRH in such women is predicated on the administration of the first dose of TRH within the first 12 postpartum hours and every 12 hours thereafter for approximately 5-10 days.
An additional use of TRH is in surrogate mothers. Studies in accordance with the present invention have involved the administration of TRH to adoptive mothers. In most instances, such women have undergone voluntary sterilization following the birth of natural children but, for one reason or another, wish to have another child. By the present invention, lactation has been induced in such women for the benefit of their adopted child by attempting to simulate the effects of pregnancy on prolactin secretion and, at the same time, by requesting that the mother practice auto-stimulation of the nipple. The technique of stimulation is as follows: Women are treated with 5 to 10 mg of conjugated estrogens equine twice a day for 14 days. Caution with regard to the possibility of side effects is given to each woman based upon the known effects of such estrogens on the vascular system. Beginning on the 7th day of estrogen treatment, oral TRH 5-10 mg twice a day, at intervals of about 12 hours, is administered for the final 7 days of treatment with estrogen. At the end of the 14th estrogen-treatment day, TRH is continued while the frequency of nipple stimulation is increased from four times daily to every 4 hours. In the women studied thus far, milk production can be induced within 72 hours following the withdrawal of the estrogen. Associated with this is an increase in the basal plasma prolactin concentration. Milk production thereafter varies depending upon the willingness of the adopted child to take the breast. It has also been found that induction of lactation is much easier in women who have previously had children although the series of women studied who have adopted children but have never been pregnant themselves is too small to draw any final conclusions
The administration of TRH may also be initiated in puerperally lactating mothers who have to undergo emergency surgery such as polycystectomy, apendectomy, or the repair of fractures. Such surgery usually takes the mother away from the child for periods of time up to 14 days and a mother who is desirous of breastfeeding may find great difficulty in reestablishing lactation when she returns home from the hospital. In such cases, the administration of TRH has been associated with the reestablishment of lactation within 48 hours. It is to be emphasized that such lactation cannot be firmly established without coincident sucking of the nipple by the child.